Bipolar Disorder

1-Definition: Bipolar disorder "manic depressive disorder or manic depression", It's a serious mental illness, can lead to risky behavior, damaged relationships and careers, and even suicidal tendencies, if it's not treated, Bipolar disorder is characterized by extreme changes in mood (poles) from mania to depression, Between these mood swings, a person with bipolar disorder may experience normal moods. "Manic" describes an increasingly "restless, energetic, talkative, reckless, powerful, euphoric period", Then, at some point, this high-flying mood can spiral into something darker "irritation, confusion, anger, feeling trapped". "Depression" describes the opposite mood "sadness, crying, sense of worthlessness, loss of energy, loss of pleasure, sleep problems". But because the pattern of highs and lows varies for each person, bipolar disorder is a complex disease to diagnose. For some people, mania or depression can last for weeks or months, even for years. For other people, bipolar disorder takes the form of frequent and dramatic mood shifts (WebMD,2008).

2-Risk factors: lifestyle habits increase the risk of bipolar disorder, that lack of sleep increases the risk of having an episode of mania, In addition, antidepressant medications, particularly when taken as the only medication, may also trigger a switch into a manic state. Excessive use of alcohol or drugs can also trigger bipolar symptoms. Research has shown that about 50% of bipolar sufferers have a substance abuse or alcohol problem. Sufferers often use alcohol or drugs to self-medicate during their high and low moods. Also environmental stress that include seasonal changes, holidays, and major life changes such as starting a new job, losing a job, going to college, family disagreements, marriage, or a death in the family, increase the risk of bipolar disorder

(WebMD,2008).

3-Epidemiology: Approximately 5% of the adult population has either bipolar I or II disorder, with the full spectrum of recurrent mood disorders (American Psychiatric Association ,2000).

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The lifetime prevalence of bipolar I disorder (one or more manic or mixed episodes) is 0.4% to 1.6%; that for bipolar II disorder (recurrent major depressive episodes with hypomanic episodes) is approximately 0.5%, Bipolar I disorder occurs equally in men and women, whereas bipolar II disorder is more common in women (American Psychiatric Association,2000 ; American Psychiatric Association,2002).

4-Etiology: The exact etiology of bipolar disorder is unknown. Bipolar disorder is thought to be a complex genetic disease that is environmentally influenced and caused by a wide range of neurobiologic abnormalities. Stressful life events, alcohol or substance use, and changes in the sleep-wake cycle can elicit the expression of genetic or biologic vulnerabilities that cause dysregulation of neurotransmitters, neuroendocrine pathways, and second messenger systems (Goldberg et al,1999). 4.1-Neurochemical theories: Dysregulation between neurotransmitters, neuropeptides, hormones, and secondary messenger systems can produce a cyclic rhythm disturbance in the central nervous system (Torrey, Knable, 2002). The "permissive serotonin hypothesis" proposes that serotonin (5-HT) plays a critical role in modulating brain activity (e.g., stabilization of the catecholamine system and inhibition of dopamine (DA) release), and is low in both mania and depression, The type of affective state that is expressed with the permissive hypothesis is determined secondarily by the level of norepinephrine (NE) (e.g., increased amounts of NE lead to mania, decreased amounts lead to depression), 5-HT deficiency and changes in the light–dark cycle may result in reduced melatonin secretion from the pineal gland that disrupts the sleep wake cycle, alters circadian rhythms, and causes seasonal affective changes (Goodnick et al, 1998; Mahmood et al, 2001). The catecholamine hypothesis of mood disorders suggests that increased DA and NE activity contribute to hyperactivity and psychosis associated with the severe stages of mania, and reduced activity causes depression (Goodnick et al, 1998; Goldberg et al, 1999). A γ-aminobutyric acid (GABA) deficiency theory has been proposed for mania as it inhibits NE and DA activity (Goodnick et al, 1998; Goldberg et al, 1999). Glutamate and aspartate, excitatory amino acid neurotransmitters, may be overactive and involved in causing manic episodes (Manji et al, 2000). 2

Cholinergic under activity has been proposed to cause mania and over activity of acetylcholine to cause depression (Goodnick et al, 1998;

Manji et al, 2000).

4.2-Summarizes the etiologic theories of bipolar disorder: 4.2.1-Genetic factors: •

80–90% of patients with bipolar disorder have a biologic relative with a mood disorder (e.g., bipolar disorder, major depression, cyclothymia, or dysthymia).

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First-degree relatives of bipolar patients have a 15–35% lifetime risk of developing any mood disorder and a 5–10% lifetime risk for developing bipolar disorder.

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The concordance rate of mood disorders is 60–80% for monozygotic twins and 14–20% for dizygotic twins.

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Linkage studies suggest that certain loci on genes and the X chromosome may contribute to genetic susceptibility of bipolar disorder.

4.2.2-Nongenetic factors: •

Perinatal insult.

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Head trauma.

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Environmental factors: Deschronization of circadian or seasonal rhythms cause diurnal variations in mood and sleep patterns and can result in seasonal recurrences of mood episodes. Changes in the sleep-wake cycle or light-dark cycle can precipitate episodes of mania or depression. Bright light therapy can be used for the treatment of winter depression and can precipitate hypomania, mania, or mixed episodes.

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Psychosocial or physical stressors: Stressful life events often precede mood episodes and can increase recurrence rates and prolong time to recovery from mood episodes.

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Nutritional factors: Deficiency of essential amino acid precursors in the diet can cause a dysregulation of neurotransmitter activity (e.g., L-tryptophan deficiency causes a decrease in 5-HT and melatonin synthesis and activity). 3

Deficiency in essential fatty acids (e.g., omega-3 fatty acids) can cause a dysregulation of neurotransmitter activity. •

Neurotransmitter/neuroendocrine/hormonal theories: Dysregulation between excitatory and inhibitory neurotransmitter systems; excitatory: NE, DA, glutamate, and aspartate; inhibitory: 5-HT and GABA.

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Monoamine hypothesis: An excess of catecholamines (primarily NE and DA) cause mania. Agents that decrease catecholamines are used for the treatment of mania (e.g., DA antagonists and α2-adrenergic agonists). Deficit of neurotransmitters (primarily NE, DA, and/or 5-HT) cause depression. Agents that increase neurotransmitter activity are used for the treatment of depression (e.g., 5-HT and NE/DA reuptake inhibitors and MAOIs).

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Dysregulation of amino acid neurotransmitters: Deficiency of GABA or excessive glutamate activity causes dysregulation of neurotransmitters (e.g., increased DA and NE activity). Agents that increase GABA activity or decrease glutamate activity are used for the treatment of mania and for mood stabilization (e.g., benzodiazepines, lamotrigine, lithium, or valproic acid).

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Cholinergic hypothesis: Deficiency of acetylcholine causes an imbalance in cholinergic-adrenergic activity and can increase the risk of manic episodes. Agents that increase acetylcholine activity can decrease manic symptoms (e.g., use of cholinesterase inhibitors or augmentation of muscarinic cholinergic activity). Increased central acetylcholine levels can increase the risk of depressive episodes. Agents that decrease acetylcholine activity can alleviate depressive symptoms (i.e., anticholinergic agents).

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Secondary messenger system dysregulation: Abnormal G protein functioning dysregulates adenylate cyclase activity, phosphoinositide responses, sodium/potassium/calcium channel exchange, and activity of phospholipases. Abnormal cyclic adenosine monophosphate and phosphoinositide secondary messenger system activity. 4

Abnormal protein kinase C activity and signaling pathways. •

Hypothalamic-pituitary-thyroid axis dysregulation: Hyperthyroidism can precipitate manic-like symptoms. Hypothyroidism can precipitate a depression and be a risk factor for rapid cycling; thyroid supplementation can be used for refractory rapid cycling and augmentation of antidepressants in unipolar depression. Positive antithyroid antibody titers reported in patients with bipolar disorder. Hormonal changes during the female life cycle can cause dysregulation of neurotransmitters (e.g., premenstrual, postpartum, and perimenopause).

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Membrane and cation theories: Abnormal neuronal calcium and sodium activity and homeostasis cause neurotransmitter dysregulation. Hypocalcemia has been associated with causing anxiety, mood irritability, mania, psychosis, and delirium. Hypercalcemia has been associated with causing depression, stupor, and coma. Extra cellular and intracellular calcium concentrations may affect the synthesis and release of NE, DA, and 5-HT, as well as the excitability of neuronal firing.

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Sensitization and kindling theories: Recurrences of mood episodes causes behavioral sensitivity and electro physiologic kindling (similar to the amygdalakindling models for seizures in animals) and can result in rapid or continuous mood cycling (Dipiro et al, 2008).

5-Clinical presentation: The essential feature of bipolar spectrum disorders are a history of mania or hypomania that is not caused by any other medical condition, substance, or psychiatric disorder. Bipolar disorder is divided into four subtypes based on the identification of specific mood episodes: bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder not otherwise specified. Mood Disorders Defined by Episodes: Disorder Subtype:

Episode(s)

Major depressive disorder, single episode

Major depressive episode

Major depressive disorder, depressive episodes Recurrent

Two or more major

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Bipolar disorder, type I depressive or mixed

Manic episode ± major episode Major depressive episode +

Bipolar disorder, type II hypomanic episode Dysthymic disorder depressive episodes Cyclothymic disorder subsyndromal depressive

Chronic subsyndromal Chronic fluctuations between and hypomanic episodes (2 years for adults

and 1 year

for children and adolescents) Mood states do not meet

Bipolar disorder not otherwise criteria for any Specified

specific bipolar disorder

The length and severity of a mood episode and the interval between episodes varies from patient to patient. Manic episodes are usually briefer and end more abruptly than major depressive episodes. The average length of untreated manic episodes ranges from 4 to 13 months. Episodes can occur regularly (at the same time or season of the year) and often cluster at 12-month intervals. Women have more depressive episodes than manic episodes, whereas men have a more even distribution of episodes. For bipolar I disorder, 90% of individuals who experience a manic episode later have multiple recurrent major depressive, manic, hypomanic, or mixed episodes alternating with a normal mood state. Approximately 5–15% of patients with bipolar II disorder will develop a manic episode over a 5-year period. If a manic or mixed episode develops in a patient with bipolar II disorder, the diagnosis is changed to bipolar I disorder. Patients with cyclothymic disorder have a 15–50% risk of later developing a bipolar I or II disorder (American Psychiatric Association,2002). 5.1-Symptoms of the depressive phase of bipolar disorder may consist of the following: Depressed mood and low self-esteem. Excessive crying spells. Low energy levels and an apathetic view of life. Sadness, loneliness, helplessness, feelings of guilt. Slow speech, fatigue, and poor coordination and concentration. Insomnia or oversleeping. 6

Thoughts of suicide or dying. Changes in appetite (overeating/not eating). Drug use: self-medication through illicit drugs. Unexplainable aching. Lack of interest or pleasure in usual activities. 5.2-Symptoms of bipolar mania or hypomania may contain: Euphoria or irritability. Excessive talking, racing thoughts. Inflated self-esteem. Unusual energy; less need for sleep. Alcohol and illicit drug use - cocaine and methamphetamines. Impulsiveness, a reckless pursuit of gratification, shopping sprees, impetuous travel, more and sometimes promiscuous sex, high-risk business investments, fast driving. Hallucinations and or delusions (in extreme cases of bipolar disorder with psychotic features) (WebMD,2008). But bipolar disorder can be sneaky, Symptoms can defy the expected manic-depressive sequence, Infrequent episodes of mild mania can go undetected, Depression can overshadow other aspects of the illness, And substance abuse can cloud the picture. Taken together, these factors make bipolar disorder surprisingly difficult to diagnose. 5.3-A few facts about bipolar disorder: As many as 20% of people complaining of depression to their doctor actually have bipolar disorder. About half of people with bipolar disorder have seen three professionals before being diagnosed correctly. It takes an average of 10 years for people to enter treatment for bipolar disorder after symptoms begun. Partly, this is due to delays in diagnosis (WebMD,2008).

6-Diagnosis and difficulties: The American Psychiatric Association has established a long list of specific criteria for recognizing the disorder. Evaluation involves investigating the patient's history and any 7

family history of mood swings or suicide. Other disorders must be ruled out particularly such childhood problems as school phobia and attention deficit disorder, aging problems of dementia, schizophrenia, schizoaffective disorder, and other psychotic states induced solely by alcohol or drugs. Drug or alcohol abuse is common in persons with bipolar disorder and can mask the symptoms, thus complicating diagnosis and treatment. Recognizing and treating any drug abuse is a priority, since it is a strong predictor of suicide, especially in men. Before treatment begins, the patient receives a careful physical exam, and blood and urine are tested to detect conditions that could put medical constraints on the choice of treatment. A thyroid analysis is particularly important both because hyperthyroidism can look like mania and because lithium "the principal drug treatment for bipolar disorder" is known to lower thyroid function and/or impair kidney function. During treatment, frequent blood tests are necessary to see that adequate drug levels have been reached and to detect adverse reactions at an early stage (WebMD,2008).

Several medical, medication-induced, or substance-related causes of mania and depression have been identified, A complete medical, psychiatric, and medication history, physical examination, and laboratory testing are necessary to rule out any organic causes of mania or depression (American Psychiatric Association,2002). 6.1-Secondary causes of mania: •

Medical conditions that induce mania:

1- CNS disorders: Brain tumor, Strokes, Head injuries, Subdural hematoma, Multiple Sclerosis, Systemic Lupus Erythematosus, Temporal lobe seizures, Huntington’s disease. 2- Infections: Encephalitis, Neurosyphilis, Sepsis, Human immunodeficiency virus. 3- Electrolyte or metabolic abnormalities: Calcium or Sodium fluctuations, Hyper or Hypoglycemia. 4- Endocrine or hormonal dysregulation: Addison’s disease, Cushing’s disease, Hyper or Hypothyroidism, Menstrual-related or Pregnancy-related or Perimenopausal mood disorders. •

Medications or drugs that induce mania: Alcohol intoxication. Drug withdrawal states (alcohol, α2-adrenergic agonists, antidepressants, barbiturates, benzodiazepines, opiates). 8

Antidepressants (MAOIs, TCAs, 5-HT and/or NE and/or DA reuptake inhibitors, 5-HT antagonists). DA-augmenting agents (CNS stimulants: amphetamines, cocaine, sympathomimetics, DA agonists, releasers, and reuptake inhibitors). Hallucinogens (LSD, PCP). Marijuana intoxication precipitates psychosis, paranoid thoughts, anxiety, and restlessness. NE-augmenting agents (α2-adrenergic antagonists, β-agonists, NE reuptake inhibitors). Steroids (anabolic, adrenocorticotropic hormone, corticosteroids). Thyroid preparations. Xanthines (caffeine, theophylline). Over-the-counter weight loss agents and decongestants (ephedra, pseudo ephedrine). Herbal products (St. John’s wort). •

Somatic therapies that induce mania: Bright light therapy. Sleep deprivation.

6.2-Secondary causes of depression: •

General medical conditions:

1-Endocrine diseases: Hypothyroidism, Addison or Cushing disease. 2-Deficiency states: Pernicious anemia, Wernicke encephalopathy , Severe anemia. 3-Infections: AIDS, Encephalitis, Human immunodeficiency virus, Mononucleosis. Sexually transmitted diseases , Tuberculosis. 4-Collagen disorder: Systemic lupus erythematosus. 5-Metabolic disorders: Electrolyte imbalance,(Hypokalemia, Hyponatremia), Hepatic encephalopathy. 6-Cardiovascular disease: Coronary artery disease, Congestive heart failure, Myocardial infarction. 7-Neurologic disorders: Alzheimer’s disease, Epilepsy, Huntington’s disease, Multiple sclerosis, Pain, Parkinson’s disease, Post stroke. 8-Malignant disease. •

Medications or drugs that induce depression:

Substance use disorders (including intoxication and withdrawal): 9

Alcoholism. Marijuana abuse and dependence. Nicotine dependence. Opiate abuse and dependence (e.g., heroin). Psychostimulant abuse and dependence (e.g., cocaine). Drug therapy: Antihypertensives: Clonidine, Diuretics, Guanethidine sulfate, Hydralazine hydrochloride, Methyldopa, Propranolol, Reserpine. Hormonal therapy: Oral contraceptives. Steroids/adrenocorticotropic hormone. Acne therapy: Isotretinoin. Other: Interferon-β1a. An accurate diagnosis is important because some psychiatric and neurologic disorders present with manic-like or depressive-like symptoms, For example, attentiondeficit/hyperactivity disorder and a manic episode have similar characteristics; thus individuals with bipolar disorder can be misdiagnosed and prescribed central nervous system stimulants. Another disease state that has a similar presentation to bipolar disorder is schizoaffective disorder. This disease is a mix between schizophrenia and bipolar disorder. Patients with schizoaffective disorder have mood episodes, but the distinguishing factor from bipolar disorder is that these patients experience psychosis even between mood episodes during periods of euthymia (Dipiro et al, 2008). 6.3-Diagnostic criteria of mood episodes: 1. Mental status examination. 2. Psychiatric, medical, and medication history. 3. Physical and neurologic examination. 4. Basic laboratory tests: complete blood count, blood chemistry screen, thyroid function, urinalysis, urine drug screen. 5. Psychological testing. 6. Brain imaging: magnetic resonance imaging and functional scan; alternative: computed tomography scan, positron emission tomography scan. 10

7. Lumbar puncture. 8. Electroencephalogram.

7-Course of illness: The average age of onset of a first manic episode is 21 years. More than 80% of bipolar patients have more than four episodes during their lifetime. Usually there is normal functioning between episodes. Rapid cyclers (10% to 20% of bipolar patients) have four or more episodes per year (major depressive, manic, mixed, or hypomanic). Rapidcycling and mixed states are associated with a poorer prognosis and nonresponse to antimanic agents. Risk factors for rapid cycling include biologic rhythm dysregulation, antidepressant or stimulant use, hypothyroidism, and premenstrual and postpartum states. Suicide attempts occur in up to 50% of patients with bipolar disorder, and approximately 10% to 19% of individuals with bipolar I disorder commit suicide. Bipolar II patients may be more likely than bipolar I patients to attempt suicide. Bipolar patients with substance abuse disorders are more likely to have an earlier onset of illness, mixed states, higher relapse rates, poorer response to treatment, higher suicide risk, and more hospitalizations. Episodes may become longer in duration and more frequent with aging (American Psychiatric Association,2002).

8-Treatment: 8.1-General principles for the management of bipolar disorder: Goals of treatment: • Eliminate mood episode with complete remission of symptoms (i.e., acute treatment). • Prevent recurrences or relapses of mood episodes (i.e., continuation phase treatment). • Return to complete psychosocial functioning. • Maximize adherence with therapy. • Minimize adverse effects. • Use medications with the best tolerability and fewest drug interactions. • Treat comorbid substance use and abuse. • Eliminate alcohol, marijuana, cocaine, amphetamines, and hallucinogens. 11

• Minimize nicotine use and stop caffeine intake at least 8 hours prior to bedtime. • Avoidance of stressors or substances that precipitate an acute episode. Treatment of bipolar disorder must be individualized because the clinical presentation, severity, and frequency of episodes vary widely among patients. Treatment approaches should include both nonpharmacologic and pharmacologic strategies (Goldberg et al,1999). Patients and family members should be educated about bipolar disorder (e.g., symptoms, causes, and course) and treatment options. Long-term adherence to treatment is the most important factor in achieving stabilization of the disorder. The treatment of bipolar disorder can vary depending on what type of episode a patient is experiencing. Once diagnosed with bipolar disorder patients should remain on a mood stabilizer (e.g. lithium, valproate) for life. During acute episodes medications can be added and then tapered once a patient is stabilized and euthymic. For example, when treating a patient for mania with psychotic features, the patient should be on a mood stabilizer and antipsychotic. If the antipsychotic is the patient’s maintenance therapy, the dose should be increased or perhaps changed altogether. If treating a patient for a severe depressive episode, add an antidepressant to the mood stabilizer and an antipsychotic if psychosis is also present (Dipiro et al, 2008). 8.2-Nonpharmacologic therapy: The basics of nonpharmacologic approaches are of adequate nutrition, sleep, exercise, and stress reduction. Sleep deprivation, high stress, and deficiencies in dietary essential amino acids, fatty acids, vitamins, and minerals can exacerbate mood episodes and result in poorer outcomes (Goldberg et al,1999). Another effective treatment is to combine medications with adjunctive psycho educational programs, supportive counseling, insight-oriented psychotherapy (individual or group), couples or family therapy, cognitive behavioral therapy, and communication enhancement training. 8.2.1-Types of psychotherapy used to treat bipolar disorder include: Behavioral therapy: This focuses on behaviors that decrease stress. Cognitive therapy: This type of approach involves learning to identify and modify the patterns of thinking that accompany mood shifts.

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Interpersonal therapy: This involves relationships and aims to reduce strains that the illness may place upon them. Social rhythm therapy: This helps them develop and maintain daily routines. Support groups also help patients with bipolar disorder, that receive encouragement, learn coping skills, and share concerns, they may feel less isolated as a result. Family members and friends may also benefit from a support group. They can gain a better understanding of the illness, share their concerns, and learn how to best support loved ones with bipolar disorder (WebMD,2008). 8.2.2-Electroconvulsive therapy (ECT) is sometimes used for severely manic or depressed patients and for those who don't respond to medication or for those women who, while pregnant, experience symptoms. Because it acts quickly, it can also help patients who are considered to be at high risk for committing suicide. ECT fell out of favor in the 1960s, but the procedure has been greatly refined since then. The patient is first anesthetized and a drug to prevent muscle contraction is given. Then an electric current is passed through the brain to produce a grand mal seizure of short duration " no more than a few seconds". During the course of ECT treatments usually two to three weeks lithium and other mood stabilizers are discontinued to ensure an adequate response to the electrical stimulation. The newer types of non-pharmocological treatments of depression are: •

VNS (Vagal Nerve Stimulation).

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TMS (Transcranial Magnetic Stimulation). Light therapy has proved effective as an additional treatment when bipolar disorder has a connection to the winter depression condition seasonal affective disorder. For those people who usually become depressed in winter, sitting for 20-30 minutes a day in front of a special light box with a full-spectrum light can effectively treat their depression (WebMD,2008).

The use of ECT for severe episodes of mania, depression, psychotic features (e.g., hallucinations or delusions), mixed episodes, or rapid cycling is still considered the best acute treatment approach for those patients who do not respond to first-line mood stabilizers such as lithium and valproate (Goldberg et al,1999). 13

8.2.3-Dietary intake: Disturbances in 5-HT neurotransmission secondary to inadequate dietary L-tryptophan or abnormalities in tryptophan hydroxylase, 5-HT transporters, and 5-HT receptors was implicated in the pathophysiology of manic depressive illness as early as 1958, If available 5-HT is low, the synthesis and secretion of melatonin can be disrupted, thus causing circadian rhythm changes (Goodnick et al, 1998). A dietary deficiency in essential fatty acids (found in certain fish oils and flaxseed oil that contains α-linolenic acid) has been proposed as a potential cause of mood disorders, Omega-3 fatty acids have been shown to suppress neuronal pathways and inhibit kindling processes by several mechanisms (e.g., inhibition of phosphatidylinositol and G-protein secondary messengers and blocking L-type calcium channels). Seafood and fish are rich dietary sources of omega-3 essential fatty acids, specifically docosahexaenoic acid and eicosapentaenoic acid (Parker et al, 2006). 8.3-Pharmacologic therapy: Pharmacotherapy is crucial for the acute and maintenance treatment of bipolar disorder and includes lithium, valproate, carbamazepine, lamotrigine, atypical antipsychotics, and adjunctive agents such as antidepressants and benzodiazepines (Dipiro et al, 2008). The term mood stabilizer is often used to describe the class of medications used in the treatment of bipolar disorder, but this may not be accurate as some medications are more effective for acute mania, some for the depressive episode, and others for the maintenance phase. Lithium, valproate (or divalproex sodium), aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone are currently approved by the Food and Drug Administration (FDA) for the treatment of acute mania in bipolar disorder; only lithium, olanzapine, and lamotrigine are approved for the maintenance treatment of bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar depression. Lithium is the drug of choice for bipolar disorder with euphoric mania, whereas valproate has better efficacy for mixed states, irritable/dysphoric mania, and rapid cycling compared to lithium (American Psychiatric Association,2002). Combination therapies (e.g., lithium plus valproate or carbamazepine; lithium or valproate plus an atypical antipsychotic) can provide better acute response and longterm prevention of relapse and recurrence than monotherapy in some bipolar patients particularly those with mixed states or rapid cycling. There are few controlled studies in children and adolescents with bipolar disorder, thus little is known about the long-term 14

efficacy and safety of specific agents or for combination therapies in this population (American Psychiatric Association,2002; Goldberg et al,1999).

8.3.1-General information regarding efficacy and safety: Lithium was first used in 1949 as a treatment for mania and was approved in 1972 in the United States for the treatment of acute mania and for maintenance therapy. Lithium was the first established mood stabilizer, and is still considered a first-line agent for acute mania and continuation treatment of bipolar I and II disorders (Goldberg et al,1999). Lithium is the only bipolar medication approved for children and adults aged 12 years and older. Long-term lithium treatment has been shown to reduce suicide risk in several studies, Patients with rapid cycling or mixed states may not respond as well to lithium monotherapy compared to some anticonvulsants Lithium requires regular assessment of renal and thyroid functioning and lithium blood level monitoring to minimize adverse effects (American Psychiatric Association,2002). Divalproex sodium (known as sodium valproate) was marketed in 1995 for the acute treatment of mania in adults and is now the most prescribed mood stabilizer in the United States. Divalproex sodium is FDA approved only for the treatment of acute manic or mixed episodes; however it is commonly used in clinical practice as maintenance monotherapy for bipolar disorder. Although carbamazepine is commonly used for both acute and maintenance therapy, it is not approved in the United States for bipolar disorder. There are some data to support the use of oxcarbazepine, a 10-keto analogue of carbamazepine, in the treatment of bipolar disorder, however it is not approved for the treatment of bipolar disorder in the United States. Valproate, carbamazepine, and oxcarbazepine each have a wide range of neurologic, gastrointestinal, electrolyte, and hematologic adverse effects that requires regular assessment and routine blood test (Dipiro et al, 2008). Lamotrigine, a newer anticonvulsant, was approved in 2003 in the United States for the maintenance treatment of bipolar I disorder (Calabrese et al, 2002; Hurley SC, 2002), Lamotrigine add-on or monotherapy has been used for treatment refractory bipolar depression (American Psychiatric Association,2002; Calabrese et al, 2002), Lamotrigine is associated with causing hypersensitivity reactions and rare life-threatening skin rashes and requires slow dosage titration (American Psychiatric Association,2002). Atypical antipsychotics such as aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone are effective as monotherapy or adjunctive therapy with lithium and valproate in the treatment of acute mania (Perlis et al, 2006), Some antipsychotics have the 15

potential to cause adverse effects such as extrapyramidal reactions, sedation, emotional blunting, sexual dysfunction, metabolic syndrome, and orthostatic hypotension (Goodnick et al, 1998; Yatham LN, 2002).

8.3.2-Alternative drug treatments: Benzodiazepines: High potency benzodiazepines such as clonazepam and lorazepam are commonly used as an alternative to or in combination with antipsychotics when patients are experiencing acute mania, agitation, anxiety, panic, and insomnia, or cannot take mood stabilizers (e.g., during the first trimester of pregnancy) (American Psychiatric Association,2002; Goldberg et al,1999).

Benzodiazepines cause minimal adverse effects compared to antipsychotics, and at higher doses, rapidly sedate agitated patients (Goldberg et al,1999), Benzodiazepines can cause central nervous system depression, sedation, cognitive and motor impairment, dependence, and withdrawal reactions. Relative contraindications for long-term therapy with benzodiazepines are drug or alcohol abuse or dependency. When no longer required, benzodiazepines should be gradually tapered and discontinued to avoid withdrawal symptoms (Dipiro et al, 2008). Antidepressants: Antidepressants are routinely added for the treatment of acute depression, but some studies have reported that specific classes such as the tricyclic antidepressants can carry an increased risk of inducing mania in bipolar I disorder and possibly cause rapid cycling (American Psychiatric Association,2002; Goldberg et al,1999). Some guidelines recommend avoiding antidepressants in the treatment of bipolar depression or limiting their use to brief intervals, but recent evidence suggests that the coadministration of mood stabilizers can reduce the risk of antidepressant induced switching (Keck et al, 2003). In general, the antidepressant should be gradually withdrawn 2 to 6 months after remission, and the patient maintained on a moodstabilizing agent (Sachs et al, 2000), For patients with recurrent depressive episodes, long-term adjunctive treatment with antidepressants can be required to avoid relapses, particularly in bipolar II disorder (American Psychiatric Association,2002; Goldberg et al,1999).

Calcium channel antagonists: Calcium channel antagonists inactivate voltagesensitive calcium channels, thus inhibiting neurotransmitter synthesis and release and neuronal signal transmission (Manji et al, 2000; Goodnick et al, 1998). 16

Nimodipine, a dihydropyridine, can be more effective than verapamil for rapid-cycling bipolar disorder because of its anticonvulsant properties, high lipid solubility, and good penetration into the brain (American Psychiatric Association,2002; Goldberg et al,1999; Manji et al, 2000; Goodnick et al, 1998).

Calcium channel blockers are generally well tolerated, and the most common adverse effects are bradycardia and hypotension. The low teratogenic effects of these agents can make them a preferable choice over lithium or anticonvulsants during pregnancy and breastfeeding (Goodnick et al, 1998).

9-Evaluation of therapeutic outcomes: The establishment and maintenance of a therapeutic alliance with a clinician is essential in monitoring a patient’s psychiatric status and safety; enhancing treatment adherence, promoting good nutrition, sleep, and exercise, identifying stressors, recognizing new mood episodes, and minimizing adverse reactions and drug interactions (Torrey, Knable, 2002).

Patients who have a partial response or nonresponse to established bipolar therapies should be reassessed for an accurate diagnosis, concomitant medical or psychiatric conditions, and medications or substances that exacerbate mood symptoms. Nonadherence to medication treatment, delusional symptoms, alcohol or substance abuse, rapid cycling, or mixed states are often associated with poorer treatment outcomes. The evaluation of therapeutic outcomes for bipolar disorder requires regular monitoring by a clinician. More frequent office visits, telephone calls, and intensive outpatient programs are first-line strategies to prevent hospitalization during the acute treatment phase of a manic or depressive episode (American Psychiatric Association,2002).

10-Women with bipolar disorder: In general, research shows that women tend to experience more periods of depression than men. In bipolar disorder, women are more likely to develop the type bipolar II meaning they never develop severe mania, but instead have milder episodes of hypomania that alternate with depression. Women are also at higher risk for rapid cycling, which means having four or more mood episodes in one year (WebMD,2008). 10.1-Bipolar disorder drugs and reproduction: 17

Mood stabilizing drugs for bipolar disorder have been linked with reproductive problems in women, specifically polycystic ovarian syndrome, a problem related to female hormones. This condition puts women at risk for infertility, diabetes, and possibly heart disease and cancer of the uterus. However, the condition is treatable with medications. Before and during pregnancy, women should not take lithium and other bipolar medications, says Michael Aronson, a clinical psychiatrist and consultant for WebMD. "The interesting thing is, sometimes pregnancy by itself will stabilize someone with bipolar disorder. At other times, it can destabilize them. The best alternative for someone who is pregnant, who is having problems with depression or mania and cannot be placed on an adequate dose of medication, is using ECT (electroconvulsive therapy). It's very effective and it's safe." (WebMD,2008). 10.2-Bipolar disorder drugs and menopause: The hormone fluctuations of perimenopause and menopause can cause mood disorders in any woman not just those with bipolar disorder. However, for those already having troubles with major depression, bipolar, or anxiety disorders there usually is an increase in symptoms during this time. Especially during perimenopause, women may be especially vulnerable to depressive symptoms because of declining estrogen levels, During menopause, hormone therapy may help. A change in antidepressant or mood stabilizing drug also may be the answer (WebMD,2008).

11-Related news: 11.1-Study shows symptoms of bipolar disorder may continue in adulthood: Oct. 6, 2008 Children who are diagnosed with bipolar disorder can continue to suffer from the disease as they develop into young adults. Barbara Geller, and her colleagues at Washington University followed a sample of children diagnosed with pediatric bipolar disorder into adulthood. Beginning in 1995 to 1998, the researchers examined 115 children diagnosed with bipolar disorder with an average age of 11. At the beginning of the study and again during nine follow-up visits conducted over eight years, the children and their parents were interviewed separately about their symptoms, diagnoses, daily cycles of mania and depression, and interactions with others. 18

During the eight-year follow-up, the researchers found that the children's first, second, and third episodes of mania included psychosis and daily cycling between mania and depression for long periods of time. Many of them recovered from these episodes, but about 73% of them relapsed. After the follow-up period, Geller and her colleagues found that about 44% of those who had bipolar disorder as children and who turned 18 by the end of the study period continue to have manic episodes as young adults. 35% of them had substance use disorders, a rate similar to those diagnosed with bipolar disorder as adults. "The study provides validation that the illness continues into adulthood in a very large proportion of the children, and unfortunately like adults with the disease, they have a high rate of substance dependence," says Geller. The study concluded that the severity and chronic nature of this disorder highlights the need for a greater effort toward understanding the neurobiology behind the disease and for developing prevention and intervention strategies. 11.2-Study shows age of dad is a factor in risk of child developing bipolar disorder: Sept. 2, 2008 A new study suggests that children born from older fathers are at increased risk of developing bipolar disorder. Overall, children born to fathers in their mid-50s and older were found to have a 37% higher risk for bipolar disorder than children born to dads in their early 20s. The risk of developing the mood disorder before the age of 20 was roughly 2.5-times greater for children born to men age 50 and older than for children born to men between the ages of 20 and 24. According to the National Institute of Mental Health, about 5.7 million American adults have bipolar disorder, a serious mental illness characterized by dramatic, episodic mood swings. While the mood disorder tends to run in families, suggesting a genetic link, little else is known about the causes of bipolar disorder. Older maternal age was associated with a slight, but nonsignificant, overall increase in risk, but no association was seen between maternal age and the risk for a bipolar diagnosis before age 20.

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The fact that paternal age appears to be a more important risk factor for bipolar disorder than maternal age suggests that genetic mutations in sperm may be to blame. Men add more mutations to the gene pool than women because their reproductive cells continue to divide throughout their lives. Women have only about 23 divisions in the cells that produce their eggs, and these divisions occur before birth, More divisions mean more potential mutations or DNA damage that could be driving the increased risk for bipolar disorder and other genetically influenced mental disorders. 11.3-Study shows family connections for bipolar disorder and schizophrenia: Jan. 15, 2009 The largest study ever to track bipolar disorder and schizophrenia within families offers evidence that the two psychiatric disorders share a common genetic cause. For more than a century the psychiatric community has debated whether schizophrenia and bipolar disorder were two distinct disorders or were more connected. Over the course of their illnesses, many patients experience similarities in certain symptoms characteristic of both, such as manic mood swings in bipolar disorder and psychosis in schizophrenia. Recent genetic studies suggest a common genetic cause for the two conditions. But earlier studies in families have not supported this conclusion, finding no increase in bipolar disorder in family members of schizophrenics and vice versa (WebMD,2008).

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12-References: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, American Psychiatric Association, 2000:382–401. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Bipolar Disorder (Revision). Am J Psychiatry 2002;159:1–50. Calabrese JR, Shelton MD, Rapport DJ, et al. Long-term treatment of bipolar disorder with lamotrigine. J Clin Psychiatry 2002;63(Suppl10):18–22. DiPiro J., Talbert R., Yee G., Matzke G., Wells B., Posey L., Pharmacotherapy A Pathophysiological Approach, seven edition, 2008. Goldberg JF, Harrow M, eds. Bipolar Disorders: Clinical Course and Outcome. Washington, DC: American Psychiatric Press, 1999. Goodnick PJ, ed. Mania: Clinical and Research Perspectives. Washington, DC: American Psychiatric Press, 1998. Hurley SC. Lamotrigine update and its use in mood disorders. Ann Pharmacother 2002;36:860–873. Judd LL, Akiskal HS. The prevalence and disability of bipolar spectrum disorders in the U.S. population: Re-analysis of the ECA database taking into account sub threshold cases. J Affect Disord 2003;73:123–131. Keck PE Jr., Nelson EB, McElroy SL. Advances in the pharmacologic treatment of bipolar depression. Biol Psychiatry 2003;53:671–679. Mahmood T, Silverstone T. Serotonin and bipolar disorder. J Affect Disord 2001;66:1– 11. Manji HK, Bowden CL, Belmaker RH, eds. Bipolar Medications: Mechanisms of Action. Washington, DC: American Psychiatric Press, 2000. Parker F, Gibson NA, Brotchie H, et al. Omega-3 fatty acids and mood disorders. Am J Psychiatry 2006;163:969–978. Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry 2006;67:509–516. 21

Sachs GS, Koslow CL, Ghaemi SN. The treatment of bipolar depression. Bipolar Disord 2000;2:256–260. Taylor L, Farone SV, Tsuang MT. Family, twin, and adoption studies of bipolar disease. Curr Psychiatry Rep 2002;4:130–133. Torrey EF, Knable MB. Surviving Manic Depression: A Manual on Bipolar Disorder for Patients, Families, and Providers. New York: Basic Books, 2002. WebMD Medical Reference with The Cleveland Clinic: "Bipolar Disorder (Manic Depressive Disorder)." WebMD Assess Plus: Bipolar Disorder Assessment. National Institute for Mental Health: "Step-BD Women’s Studies." Massachusetts General Hospital Bipolar Clinic & Research Program. MedicineNet.com: "Bipolar Disorder (Mania)." WebMD Medical Reference with The Cleveland Clinic: "Effects of Untreated Depression." American Psychiatric Association: "Practice Guideline for the Treatment of Patients With Bipolar Disorder." Reviewed by Amal Chakraburtty, MD on July 22, 2008. Yatham LN. The role of novel antipsychotics in bipolar disorders. J Clin Psychiatry 2002;63(Suppl3):10–14.

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